JB Minireview—Functions of MAP Kinase Cascades J. Biochem.

136, 557–561 (2004)

DOI: 10.1093/jb/mvh159

Regulatory Mechanisms and Function of ERK MAP Kinases

Satoru Torii, Kei Nakayama, Takuya Yamamoto and Eisuke Nishida*
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto
606-8502

Received September 18, 2004; accepted September 18, 2004

Spatiotemporal control of the Ras/ERK MAP kinase signaling pathway is a key factor
for determining the specificity of cellular responses including cell proliferation, cell
differentiation and cell survival. The fidelity of this signaling is regulated by docking
interactions as well as scaffolding. Subcellular localization of ERK is controlled by
cytoplasmic ERK anchoring proteins that have a nuclear export signal (NES), such as
MEK. In quiescent cells, ERK and MEK localize to the cytoplasm. In response to stim-
ulation, dissociation of the MEK-ERK complex is induced and activated ERK translo-
cates to the nucleus. Recently, several negative regulators for Ras/ERK signaling

Downloaded from http://jb.oxfordjournals.org/ at Fachbereichsbibliothek on September 14, 2014

have been identified and their detailed molecular mechanisms have been analyzed.
Among them, Sprouty and Sef act as a temporal and a spatial regulator, respectively,
for Ras/ERK signaling. Thus, multiple factors are involved in control of Ras/ERK sig-
naling.

Key words: docking interaction, negative regulator, nuclear export signal, nuclear
translocation, spatiotemporal control.

Overview Scaffolding proteins interact with several components

The Ras/ERK MAP kinase signaling pathway is highly of the MAPK cascades to tether both enzymes and sub-
conserved throughout evolution, and plays an important strates specifically to achieve accurate signal transduc-
role in various cellular responses including cell proliferation, tion (10). KSR and MP-1 are known to function as an
cell differentiation and cell survival (1–5). Many studies ERK scaffold. Actually, these molecules have been
about regulation of Ras/ERK signaling have been reported. reported to associate with several components of the
Spatiotemporal control of this signaling is a key factor for ERK signaling pathway and to enhance ERK activation
determining the specificity of cellular responses (6–8). (17, 18). The JNK-interacting protein (JIP) family is also
a well-known scaffold protein family (10). The JIP pro-
The fidelity of ERK MAP kinase signaling teins bind to JNK, MKK7 and members of the mixed-lin-
The MAP kinase (MAPK) cascades convey signals in
eage protein kinase (MLK) group. In addition, a recent
the form of phosphorylation events. Therefore, MAPKs
report showed that JIP1 and JIP2 also interact with
form a complex with their cognate MAPKKs, substrates
MKP-7 (19). Thus, JIP scaffold complexes include both
and phosphatases. There are three major subgroups of
the MAPK family: ERK, p38 and JNK/SAPK. These activating and inhibitory components of the JNK signal-
members are activated by different stimuli and are ing pathway (Fig. 1, right).
involved in signaling to different responses through dif- Through these molecular mechanisms described above,
ferent pathways. In order to achieve the specificity and MAPKs react with appropriate partners to avoid undesir-
efficiency of the enzymatic reaction, there are two main able outcomes. Therefore, the docking interaction and the
mechanisms in the MAP kinase cascades: the docking scaffolding may regulate not only the efficiency and spe-
interaction and the scaffolding (9, 10). cificity of the cascade but also the ordered and integrated
MAPKs utilize the common docking (CD) domain for signaling.
docking interactions with MAPKKs, MAPKAPKs and
phosphatases (11). The CD domain is featured by a clus-
ter of negatively charged amino acids and is located in
the C-terminal portion of MAPKs in the primary sequence.
MAPKs have another site called the ED site, near the CD
domain in the steric structure, which could determine the
docking specificity towards MAPKAPKs (12). In addition,
hydrophobic regions of MAPKs are also important for
docking interactions (13–16). All of these docking sites
locate outside the catalytic domain and determine the
specificity of interacting molecules (Fig. 1, left).
Fig. 1. In the MAPK cascade, two kinds of mechanisms for
determining the efficiency and specificity are used. The
docking interactions are achieved through the docking groove
*Towhom correspondence should be addressed. Tel: +81-75-753-4230, including the CD domain and the ED site (left). The scaffold protein
Fax: +81-75-753-4235, E-mail: [email protected] tethers several components of the JNK signaling pathway (right).

Vol. 136, No. 5, 2004 557 © 2004 The Japanese Biochemical Society.
558 S. Torii et al.

MAPK may be evolutionarily conserved. Further studies

are required to elucidate the mechanism for nuclear
import of other MAPK family members.
To prepare the subsequent stimulation, ERK must
relocalize to the cytoplasm. This relocalization of ERK
could be achieved by an NES-dependent nuclear export.
MEK, which mostly localizes to the cytoplasm due to its
NES, can shuttle between the cytoplasm and the nucleus.
It has been suggested that the relocalization of inactive
ERK involves MEK-dependent active transport; MEK
transiently enters the nucleus and binds inactive ERK to
export it from the nucleus (29). The regulation of subcel-
lular localization of ERK should be crucial for specific cel-
lular responses to extracellular stimuli.

Temporal control of ERK signaling by Sprouty1/2

Sprouty and Sprouty-related protein with EVH-1

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domain (Spred) have been identified as conserved inhibi-
tors for Ras/ERK MAP kinase signaling (30–37). Recent
studies have demonstrated detailed molecular mecha-
nisms of action of Sprouty or Spred (37–49). Spred inhib-
its Ras/ERK signaling at the level of Raf by binding to
Fig. 2. A model for nuclear translocation of ERK. The activa- Ras and Raf (37). However, the action mechanism of
tion of the ERK pathway results in the phosphorylation of ERK and Sprouty has been controversial.
the subsequent dissociation of ERK from MEK. Dissociated ERK Sprouty proteins bind various proteins. We have
translocates from the cytoplasm to the nucleus by three pathways; reported that Sprouty1/2 becomes phosphorylated on a
(A) active transport of a dimer, (B) passive diffusion of a monomer conserved tyrosine residue (Y53 in Sprouty1 or Y55 in
and (C) transport mediated by direct interaction of ERK with the
Sprouty2) in their amino-terminal domain in a stimulus-
nuclear pore complex.
dependent manner (Fig. 3 top left) and binds to Grb2 (40).
This binding prevents Grb2 from binding to either FRS2
Subcellular localization of ERK or Shp2, leading to inhibition of Ras/ERK signaling.
MAPKs dramatically change their subcellular localiza- Moreover, we have shown that Sprouty1/2 would be
tion upon the extracellular stimuli. In quiescent cells, dephosphorylated by Shp2 (47). Other several reports
ERK localizes to the cytoplasm. This cytoplasmic locali- have indicated that Sproury2 becomes phosphorylated on
zation of ERK is mediated by its specific binding to classi- the same conserved tyrosine in a stimulus-dependent
cal MAPKKs, MEK1 and MEK2, which localize to the manner, and becomes bound to c-Cbl, the E3 ubiquitin
cytoplasm. The cytoplasmic localization of MEK is ligase (43–45, 49). This association results in polyubiq-
achieved by its NES sequence in its amino-terminal uitylation and subsequent degradation of Sprouty2 by
domain (20). In addition to MEK, PEA-15, which also the proteasome. In EGF signaling, c-Cbl normally binds
contains NES, binds ERK and retains ERK in the cyto- to the activated EGF receptor and promotes its polyubiq-
plasm (21). uitylation and subsequent degradation. However, bind-
Phosphorylation of ERK induced by extracellular stim- ing of Sprouty2 to c-Cbl inhibits this function of c-Cbl. As
uli, such as growth factors, leads to dissociation of ERK a result, Sprouty2 enhances EGF signaling in contrast
from MEK. The dissociated ERK translocates from the with its function in FGF signaling (41, 43–45). The other
cytoplasm to the nucleus. There are three pathways for group reported that the carboxy-terminal cysteine-rich
the nuclear import of ERK; (i) passive diffusion of a mon- domain of Sprouty4 binds to Raf1 (46). This interaction
omer, (ii) active transport of a dimer, which is mediated inhibits VEGF-induced activation of Raf, but not Ras-
by the low molecular weight GTPase Ran and the impor- induced one. As Sprouty4 does not become phosphor-
tin-β family protein(s), and (iii) Ran/importin-β family- ylated in response to FGF or EGF stimulation (40, 49),
independent transport, which is mediated by direct inter- the action mechanism of Sprouty4 could be different from
action of ERK with the nuclear pore complex (Fig. 2 and that of Sprouty1/2. Nevertheless, the conserved tyrosine
Refs. 22–25). In the nucleus, ERK phosphorylates and residue in their amino-terminal domain appears to be
activates several nuclear targets such as transcription required for Sprouty proteins’ inhibitory activity. Mutant
factors. Nuclear localization of ERK appears to be prereq- Sprouty proteins in which the conserved tyrosine residue
uisite for proper cellular responses (26). The nuclear (Y53 in Sprouty1/4 or Y55 in Sprouty2) is mutated act as
accumulation of ERK may require an unidentified a dominant-negative form (39, 40, 49). By using this dom-
nuclear anchor(s) (27). The nuclear anchor(s) may be a inant-negative form of Sprouty, we have found that
short-lived protein synthesized by the ERK pathway acti- Sprouty1/2 could control the duration of ERK activity
vation. Interestingly, in fission yeast, the nuclear import (40). Overexpression of Sprouty1 results in transient
of stress-activated MAPK Spc1 is coupled with its dissoci- ERK activation, whereas overexpression of Sprouty1
ation from MAPKK Wis1, and the nuclear retention of Y53F results in sustained ERK activation (Fig. 3, top
Spc1 requires a nuclear anchor (28). Therefore, several right). Correspondingly, overexpression of Sprouty1
aspects of the mechanism of nuclear translocation of Y53F or Sprouty2 Y55F in PC12 cells enhances FGF-

J. Biochem.
Spatiotemporal Control of ERK Signaling 559

Fig. 3. Spatiotemporal control of Ras/

ERK signaling. Sprouty (Spry) is phos-
phorylated and activated in a stimulus-
dependent manner (top left). Sprouty
controls the duration of ERK activation
and provides temporal control for ERK sig-
naling (top right). Sef provides spatial
control for ERK signaling. Sef inhibits dis-
sociation of the MEK/ERK complex and
retains activated ERK on the Golgi appa-
ratus. Thus Sef specifically inhibits ERK
nuclear translocation without inhibiting
its activity in the cytoplasm (bottom).

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induced neurite outgrowth. Thus Sprouty provides tem- translocation. Furthermore, we have found that Sef
poral control for Ras/ERK signaling. inhibits phosphorylation of nuclear ERK substrates with-
out affecting phosphorylation of cytoplasmic ERK sub-
Spatial control of ERK signaling by Sef strates. Sef inhibits stimulus-dependent phosphorylation
Recently, Sef, a putative transmembrane protein, was of Elk-1, a nuclear target of ERK, but does not inhibit
identified in zebrafish as a negative feedback inhibitor phosphorylation of RSK2, a well-known ERK substrate
for Ras/ERK signaling (50, 51). Sef has been identified in in the cytoplasm. Downregulation of endogenous Sef by
other vertebrates and thus is thought to be a conserved siRNA enhances stimulus-induced ERK nuclear translo-
inhibitor for Ras/ERK signaling (50–54). However, there cation and the expression level of ERK target genes, such
are contradicting reports concerning the action point of as c-fos without affecting phosphorylation of both ERK
Sef. Several reports indicate that Sef acts downstream of, and RSK2. Thus we propose that Sef is a specific inhibi-
or at MEK and inhibits phosphorylation of ERK (50, 55, tor of Ras/ERK signaling to the nucleus by targeting ERK
56). In contrast, other reports argue that Sef inhibits to the cytoplasm (Fig. 3, bottom) and provides spatial
FGF signaling upstream of Ras by binding to FGF recep- control for Ras/ERK signaling.
tor (57, 58)
Most recently, our analyses have shown that Sef acts Conclusion and future prospects
as a spatial regulator for Ras/ERK signaling by specifi- As describe above, spatiotemporal control of ERK MAP
cally blocking ERK nuclear translocation without inhibit- kinase signaling is finely regulated by multiple factors,
ing its activity in the cytoplasm (59). Immunoprecipita- such as Sprouty and Sef. Sprouty is phosphorylated in a
tion assays have shown that Sef binds to the MEK-ERK stimulus-dependent manner and provides temporal con-
complex. Rather surprisingly, the binding of Sef to the trol for ERK signaling. The next challenges may include
MEK-ERK complex did not inhibit the phosphorylation elucidation of control mechanisms of ERK signaling by
or the kinase activity of ERK. Moreover, in immunofluo- Sprouty in vivo. Sef binds to active MEK, and targets
rescence experiments, Sef colocalized with activated ERK ERK to the cytoplasm. Therefore, Sef provide spatial con-
as well as activated MEK mainly on the Golgi apparatus trol of ERK signaling. The next challenges may include
in stimulated cells. Recent reports suggested that part of elucidation of regulatory mechanisms of Sef.
Ras is localized and activated on the Golgi apparatus in
response to EGF stimulation (60–62). Sef on the Golgi
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